Basic esters of substituted beta-hy-droxypropionic acids



United States Patent BASIC ESTERS F SUBSTITUTED BETA-HY- DROXYPROPIONICACIDS Frederick F. Blicke, Ann Arbor, Mich., assignor to Regents of TheUniversity of Michigan, Ann Arbor, Mich, a corporation of Michigan NoDrawing. Application September 8, 1958 Serial No. 759,383

26 Claims. (Cl. 260-.-332.2)

about 10 carbon atoms.

Pharmacological evaluation of these new compounds in the form of theirwater-soluble non-toxic salts by the Magnus method has indicated theirusefulness as antispasmodic agents. They can be prepared for use asantispasmodic agents in the same way as other natural or syntheticantispasmodics such a atropine sulfate, adiphenine hydrochloride, andthe like.

In the above formula, Ar, when a carbocyclic aromatic radical of 1-2rings having less than about 15 carbon atoms, stands for a radical ofthe benzene, naphthalene or biphenyl series. The aromatic nucleus can beun substituted, or it can be substituted by one or more substituents.Thenature of the aromatic nucleus is not critical except insofar as thesubstituents must be inert toward the reagents used in the synthesis ofthe'compounds, in particular toward organometallic compounds. Thus thesubstituents can include such substituents as alkyl, alkoxy andalkyhnercapto radicals. but not carboxy, cyano, hydroxy, primary aminoand secondary amino radicals. On this basis, a preferred class of Ar forthe invention consists of unsubstituted phenyLnaphthyl and biphenylradicals, and such radicals substituted by from one to threesubstituents selected from the class consisting of lower-alkyl groupshaving. froml to about 6 carbon atoms, lower-alkoxy groups having from 1to about v6 carbon atoms and lowerealkylmercapto groups having from 1 toabout 6 carbon atoms. Furthermore, said substituents can be in any oftheavailable positions of the aromatic nucleus and where more than one,can be the same or different. Ar can therefore represent such groups asphenyl, p-tolyl, m-methoxyphenyl, p-methylmercaptophenyl,3,4-dimethoxyphenyl, p-xenyl, l-naphthyl, 2-naphthyl, Z-thienyl,3-thienyl, 3-methyl-2-thienyl, 3,4 dimethyl-2-thienyl, and the like.

Y represents a lower-alkylene ,group or bridge having from 2 to about 5carbon atoms and thus includes the straight chain polymethyleneradicals, (CH where n is 2-5, and branched chain radicals including suchgroups The N=B portion of the molecule stands for a 2,922,795. PatentedJan 26, 1960 ice 2 tertiary-amino radical of the aliphatic orcycloaliphatic type and includes di-loWer-alkylamino, polymethyleniminoand morpholino radicals. The alkyl groups of the di-lower-alkylaminoradicals can be the same or different and each has less than about eightcarbon atoms, the dilower-alkylamino radicals thus including such groupsas dimethylamino, diethylarnino methylethylamino, dipropylamino,diisopropylamino, dibutylamino, dipentylamino, dihexylamino,diheptylamino, and the like. The polymethylenimino radicals are simplycases where the alkyl groups of the di-lower-alkylamino groups arejoined to produce a heterocyclic ring. The rings are 5- to 8- memberedand thus include pyrrolidino, piperidino,'hexamethylenimino andheptamethylenimino radicals and 'lower-alkylated derivatives thereof.

R represents, inter alia, a lshydroxyalkyl group having between 4 andabout 15 carbon atoms. The numeral 1 o f l-hydroxyalkyl means that thehydroxy group is attached to thefirst carbon atom of the 'alkyl groupwhich is the carbon atom immediately adjacent to the carbon atom bearingthe aromatic substituent, AL The l-hydroxyalkyl group may be straight orbranched. R thus includes such groups as l-hydroxybutyl,l-hydroxyisobutyl, l-hydroxyl-methylpropyl, l-hydroxy-l-ethylpropyl,1-hydroxy-2- methylbutyl, l-hydroxyhexyl, l-hdroxydecyl, l-hydroxyl-hexylheptyl, and the like.

R also can represent a I-hydroxycycloalkyl group having between 5 andabout 10 carbon atoms. The numeral 1 of 'l-hydroxycycloalkyl means thatthe hydrorry group is attached to the first carbon atom of thecycloalkyl group whichv is the carbonatom immediately adjacent to thecarbon atom bearing the phenyl substituent. In the l-hydroxycycloalkylgroup the rings 'have from 5 to 8 members and these can be substitutedby lower-alkyl corresponding acids, RCH(-Ar) -COOH. The acids themselvesare prepared in the following general manner: the acid, ArCH COOH, or ametallic salt thereof is caused to react with an alkylmagnesium halideto produce an organometallic derivative, XMgCH(Ar)COOM, Where X- ishalogen and M is a cation. The cation M is a simple. metal ion if a saltof the acid is used as the starting material, and is halomagnesium ifthe free acid/is used. The organometallic complex when reacted with analiphatic aldehyde or ketone gives, after acidification,

the desired substituted p-hydroxypropionic acid. The

reaction of the organometallic complex and the carbonyl compound iscarried out in a solvent inert under the conditions of the reaction,e.g., ether, benzene, toluene, or the like, preferably at a temperaturebetween about 20 and C.

The estersof the invention, having the general formula R-CH(Ar)-COO-Y-N=B, as described above, are prepared from the free acid'by one of thefollowing methods:

(1) The acid, RCH(Ar)-COOH, is reacted witha tertiaryamino'alkanolusing-a'mineral acid, such as sulfuric acid, as a catalyst, present inan amount greater than that necessary to neutralize the amino alcohol.The sulfate or bisulfate salt of the basic ester is formed, and the freebasic ester can be obtained by addition of alkali to the reactionmixture.

' (2) The acid, R-CH(Ar)--COOH, is heated with a tertiaryaminoalkylhalide; of the I formula ZY--N=B, where Z ishalogen (preferably chlorineonbromine) The temperature at which the reactants are heated ispreferably between about 50 C. and 150 C. A hydrohalide of the basicester is obtained which can be converted to the free basic ester by theaddition of alkali to the reaction mixture.

t (3) A metallic salt of the acid, R-CH(Ar)--COOH, is heated or simplymixed with a tertiary-aminoalkyl halide, ZYN=B, where Z is halogen. Inthis case the free basic ester is formed directly.

. These new basic esters are most conveniently used in the form ofwater-soluble acid-addition or quaternary ammonium salts, and thesesalts are within the purview of the invention. The acids which can beused to prepare acid-addition salts are those which arepharmacologically acceptable, i.e., those-which produce when combinedwith the basic esters, salts whose anions are relatively innocuous tothe animal organism in therapeutic doses of the salts, so that thebeneficial physiological properties inherent in the basic esters are notvitiated by side-effects ascribable to the anions. Appropriateacidaddition salts are those derived from mineral acids such ashydrochloric acid, hydrobromic acid, hydriodic acid and sulfuric acid;and organic acids such as acetic acid, citric acid and tartaric acid.The quaternary ammonium derivatives are obtained by the addition to thefree ,base of an ester of a strong acid, said ester having a molecularweight below about 250. A preferred class of ,qnaternizing agentsinclude lower-alkyl, lower-alkenyl or lower-aralkyl esters of stronginorganic acids or organic sulfonic acids, including such compounds asmethyl chloride, methyl bromide, methyl iodide, ethyl bromide, propylchloride, benzyl chloride, benzyl bromide, methyl sulfate, methylbenzenesulfonate and methyl ptoluenesulfonate.

All salts, whether toxic or non-toxic, are, however, useful asintermediates in the purification of the free bases or in the formationof other salts by ion exchange procedures. They also serve ascharacterizing derivatives of the free bases.

The following examples will further illustrate the in- :vention, withoutthe latter being limited thereby.

EXAMPLE 1 (a) a-(l-hydroxy-l-cyclohexyl)- z-phenylacetic acid:-Magnesium (26.7 g., 1.10 moles) was placed in a thoroughly driedtwo-liter, three-necked flask fitted with a condenser, dropping funneland stirrer. Enough dry ether was added to cover the magnesium followedby the addition of 1 cc. of ethyl bromide. After the reaction had begunthere were added, successively, about 700 cc. of dry ether and 87.0 g.(0.55 mole) of sodium phenylacetate (which had been dried at 130 C.).The mixture was stirred, and 86.4 g. (1.10 moles) of isopropyl .mixturewas cooled to about C. and, with stirring,

113.0 g. (1.15 moles) of cyclohexanone in 300 cc. of: dry ether wasadded dropwise. After the cyclohexanone had been added the mixture wasrefluxed for three -hours. The mixture was then cooled and hydrolyzed byvery careful addition of water followed by dilute hydrochloric acid. Theether layer was separated, and the aqueous layer was extracted'withether. The combined ether layers were then extracted with sodiumcarbonate solution.

Thebasic extracts were combined and carefully acidified with dilutehydrochloric acid. The acidic material which separated was extractedseveral times with ether and the combined ether extracts were dried overanhydrous magnesium sulfate. The ether was removed by distillation, andthe residue (108.0 g., 83.8% yield) was 1 recrystallized from toluenegiving a-(l-hydroxy-l-cyclo- *hexyD-e-phenylacetic acid, M.P. l3. 9 C! A-s n A solution of 4.67 g. (0.02 mole) ofa-(l-hydroxy-lcyclohexyl)-a-phenylacetic acid, prepared in part (a)above, and 3.4 g. (0.025 mole) of Z-diethylaminoethyl chloride in cc. ofisopropyl alcohol was refluxed for twelve hours. The isopropyl alcoholwas refluxed ,for twelve hours. The isopropyl alcohol was then removedunder reduced pressure, and ether was added to the oily residue whichthen solidified. Recrystallization of this material (5.7 g., 77.0%yield) from methyl ethyl ketone gave 2-diethylaminoethyla-(l-hydroxy-l-cyclohexyl)-aphenylacetate in the form of thehydrochloride which melted at 136.5-1375" C.

Analysis.-Calcd. for C H O NCI: Cl, 9.59; N, 3.79. Found: Cl, 9.66; N,3.77.

(c) The methobromide salt of Z-diethylaminoethyl a-(l-hydroxy-l-cyclohexyl)-u-phenylacetate was obtained by the addition ofa 25% excess of methyl bromide to a solution of 3.0 g. of the free basedissolved in a mixture of alcohol and ether. After twenty-four hours atroom temperature, the 3.1 g. of white crystalline compound which hadprecipitated was filtered and recrystallized from isopropyl alcohol,giving Z-diethylaminoethyl a-( l-hydroxy-l-cyclohexyl) -u-phenylacetatemethobromide, melting at 192-193" C. (dec.)

Analysis.Calcd. for C H O NBrz Br, 18.66; N, 3.27. Found: Br, 18.64; N,3.22.

Z-diethylaminoethyl ot-(1-hydroxy 1 cyclohexyl) aphenylacetatemethobromide was found to have an antispasmodic activity about 83% thatof atropine sulfate when tested by the modified Magnus method [Luduenaand Lands, J. Pharmacol. and Exptl. Therap. 110, 282 (1954)]. The ALDvalue (the approximate dose lethal to 50% of the animals tested) whenadministered intravenously to mice was 13 mg. per kg. of body weight.

EXAMPLE 2 (a) Z-hexamethyleniminoethanol: Ethylene chlorohydrin (63.0g., 0.782 mole) was added dropwise over a period of one and one-halfhours, with periodic shaking, to 77.5 g. (0.782 mole) ofhexamethylenimine [Ruzicka et al., Helv. Chim. Acta 32, 544 (1949)]heated on a steam bath. The mixture was then heated for an additionalten hours, cooled, and the brown solid which separated was treated witha solution of 35.0 g. (0.875 mole) of sodium hydroxide in cc. of water.The mixture was extracted four times with a total of 200 cc. of henzene,the benzene portions were combined and dried over anhydrous potassiumcarbonate. The mixture was filtered, the solvent removed and the residuedistilled under reduced pressure giving 71.1 g, (63.6%) of2-hexamethyleniminoethanol, B.P. 114 C. (23 mm.).

The hydrochloride was prepared from a portion of the base in ether towhich an ethereal solution of hydrogen chloride was added. The whiteprecipitate thus obtained was recrystallized from butyl alcohol, givingZ-hexamethyleniminoethanol hydrochloride, M.P. 118-120 C.

Analysis.-Calcd. for C H ONCl: Cl, 19.73; N, 7.80. Found: Cl, 19.65; N,7.77.

(b) 2 hexamethyleniminoethyl chloride hydrochloride:Hexamethyleniminoethanol (40.0 g., 0.28 mole), obtained in part (a)above, dissolved in 25 cc. of benzene, was added dropwise to a stirredsolution of 41.5 g. (0.35 mole) of thionyl chloride in 25 cc. ofbenzene. An exothermic reaction took place and the solution turned dark.After the addition the solution was refluxed for three hours, cooled,and the crystalline product was filtered and washed with benzene; yield50.8 g. (91.5%). The product was recrystallized from isopropyl alcoholgiving 2-hexamethyleniminoethyl chloride hydrochloride,

.meltingat 202.204 C.

Analysis.Calcd. forC H Ncl C1, 35.79;N, 7.07.

.Found: Cl, 35.60; N, 7.03.

(c) 2-hexamethyleniminoe'thyl (l-hydroxy-l-cyclohexyl)-phenylacetate:

A cooled solution of 1.5 g. (0.0375 mole) of sodium hydroxide in 25 cc.of water was added carefully to 5.95

The

tion of .4 g. (0.023 mole) of (1-hydroxy-1-cyclohexyl)- phenylaceticacid, as prepared in Example 1, part (a), in 75 cc. of isopropylalcohol, and the solvent was distilled through a 15 cm. Vigreaux columnuntil the vapor temperature reached 80 C. The column was replaced .by areflux condenser and the solution was refluxed for ten hours. The hotsolution was filtered, and the product precipitated from the filtrateafter cooling. The 7.85 g. (85%) of compound thus obtained wasrecrystallized from isopropyl alcohol, giving 2-hexamethylenimin0ethyl(l-hydroxy-l-cyclohexyl)-phenylacetate in the form of .itshydrochloride, which melted at 184185 C.

Analysz s.Calcd. for C H O NCl: Cl, 8.96; 'N, 3.54.

'Found: Cl, 8.88; N, 3.53.

EXAMPLE 3 (a) (1 -'hydroxy l cyclohexyl) (2 thienyDacetic acid wasprepared starting with 4.9 g. (0.2 mole) of magnesium, 16.4 g. (0.1mole) of sodium (2-thienyl)acetate in 150 cc. of ether, and 15.7 g. (0.2mole) of isopropyl chloride in 50 cc. of ether according to the methoddescribed in Example 1, part (a). After the mixture had refluxed forseveral hours, it was cooled, and 21.6 g. (0.22. mole) of cyclohexanonein 50 cc. of ether was added. The preparation was continued and workedup as described in Example 1, part (a), giving 18.5 g. (77%) of(l-hydroxy-l-cyclohexyl)-(2-thienyl)acetic acid, M.P. 108-110 C. whenrecrystallized from a benzene-petroleum ether mixture.

Neut. equiv. calcd. for C H O S: 240.3. 240.3.

(b) 2-diethylaminoethyl (l-hydroxy-l-cyclohexyl)-(2- thienyl) acetate:

Found CHzCHz CH2 CCHCOOCH2CH2N(C2H5)2 \CHZCHZ OH 1 A solution of 5.3 g.(0.022 mole) of (l-hydroxy-l-cyclohexyD-(Z-thienyl)acetic acid, asprepared in part (a) above, and 3.8 g. (0.028 mole) of2-diethylaminoethyl chloride in 75 cc. of isopropyl alcohol was refluxedfor eight hours. The warm solution was filtered and .the solvent removedfrom the filtrate. After the oily residue had been rubbed under etherfor a short period, it solidified giving 6.6 g. (79.5%) of2-diethylaminoethyl (l-hydroxy-l-cyclohexyl)-(2-thienyl) acetatehydrochloride, M.P. 123-125 C. when recrystallized from methyl ethylketone.

Analysis.Calcd. for C H O NClS: Cl, 9.43; N, 3.73. Found: Cl, 9.53; N,3.66.

EXAMPLE 4 (a) (l-hydroxy l-cyclohexyl)-(3-thienyl)acetic acid wasprepared starting-with 4.9 g. (0.2 mole) of magw .propyl alcohol wasrefluxed for fourteen hours.

described in Example 1, part (a). After the mixture had refluxed forfour hours, it was cooled, and 21.6 g. (0.22 mole) of cyclohexanone wasadded. After the addition, the contents were refluxed for two hours andworked up as described inExarnple 1, part (a), giving 17.8 g. :(74%) of(l-hydroxy-l-cyclohexyl)-(3-thienyl) iaceticacid, M.P. 130.5131.5 C.when recrystallized from a benzene-petroleum ether mixture.

Neut. equiv. calcd. for S H O S: 240.3. .Found: 241.3.

(b) 2 diethylaminoethyl (1-hydroxy-1-cyc1ohexy1)- (3-thienyl) acetate:

CHzCHa A solution of 5.4 g. (0.0225 mole) of'(l-hydroxy-1-cyclohe'xyl)-(3-thienyl)acetate acid and 3.8 g. (0.028 mole) ofZ-diethylaminoethyl chloride in 100 cc. of iso- The solution wasfiltered while hot and allowed to cool, whereupon a white precipitateformed which was collected by filtration and washed with ether, giving7.3 g. (86.5%) of 21diethylaminoet'hyl (l-hydroxy-l-cyclohexyl)-(3-thienyDacetate hydrochloride, M.P. 143-145 C. when recrystallized fromisopropyl alcohol.

Analysis.-Calcd. for C1QH3OO3NCISZ Cl, 9.43; N, 3.73. Found: Cl, 9.55;N, 3.69.

EXAMPLE 5 '99-100" C. when recrystallized from a benzene-petroleum ethermixture.

Neut. equiv. calcd, for C H 0 220.3. Found: 2200.

(b) 2 diethylaminoethyl'(l-hydroxy-l-cyclopentyl)- phenyl acetate Asolution of 5.0 g. (0.0227 .mole) of(l-hydroxy-lcyclopentyl)-phenylacetic acid as-prepared in part (a)above, and 318 g. (0.028 mole) of 2-diethylaminoethyl chloride in 75 cc.of isopropyl alcohol was refluxed for ten hours, filtered, and thesolvent removed under reduced pressure. The-addition of anhydrous etherto the gummy residue converted it to a white powder, which was collectedby filtration and washed with ether, giving 7.2 g. (89%) ofZ-diethylaminoethyl (l-hydroxy-l-cyclopentyl)- phenylacetate as thehydrochloride, M.P. 133135 C. when recrystallized from an isopropylalcohol-isopropyl ether mixture.

Analysis.Calcd. for C H O NCl: Cl, 9.96; N, 3.94. Found: Cl, 10.05; N,3.89.

EXAMPLE 6 (a) (l-hydroxy-l-cyclopentyl)-(2-thienyl-acetic acid wasprepared starting with 4.9g. (0.2 mole) of-magnesium, 16.4 g. (0.1 mole)of'soclium (2-thienyl aceonion:

o-orr-o oooniomNcoinm cmorn on A solution of 5.1 g. (0.0225 mole) of(l-hydroxy-lcyclopentyl)-(2-thienyl)acetic acid and 4.05 g. (0.03 mole)of Z-diethylaminoethyl chloride in 75 cc. of isopropyl alcohol wasrefluxed for fifteen hours. The warm solution was filtered and thesolvent removed under reduced pressure. The residue was triturated withether and the resulting solid was collected by filtration, giving 7.2 g.(88.4%) of Z-diethylaminoethyl(l-hydroxy-lcyclopenyl)-(2-thienyl)acetate hydrochloride, M.P.1'01.5103.5 C. when recrystallized from methyl ethyl ketone.

Analysis.Ca1cd. for ClqHzgOgNClSI Cl, 9.80; N, 3.87. 'Found: Cl, 9.71;N, 3.90.

EXAMPLE 7 (a) (1 hydroxy I-cyclohexyl)-(p-xenyl)acetic acid was preparedstarting with 4.9 g. (0.2 mole) of magnesium, 23.4 g. (0.1 mole) ofsodium (p-xenyl)acetate, 15.7 g. (0.2 mole) of isopropyl chloride and200 cc. of ether according to the method described in Example 1, part(a). After the mixture had refluxed for four hours, it was cooled to 10C., and 21.6 g. (0.22 mole) of cyclohexanone in 50 cc. of ether wasadded. The preparation was continued and worked up as' described inExample 1, part (a), giving 25.8 g. (83.2%) of(l-hydroxyl-cyclohexyl)-(p-xenyl)acetic acid, M.P. 215216 C.

when recrystallized from dioxane.

Neut. equiv. calcd. for C H O 310.4. 310.0.

Y e (b) 2 diethylaminoethyl (1-hydroxy-1-cyclohexyl)- (p-xenyl) acetate:

Found I A solution of 5.0 g. (0.016 mole) of(l-hydroxy-lcyclohexyU-(p-xenyl)acetic acid and 2.9 g. (0.0215 mole) 'ofZ-diethylaminoethyl chloride in 125 cc. of isopropyl alcohol wasrefluxed for fifteen hours. The hot solution was filtered, and the esterhydrochloride precipitated when the solution cooled, giving 6.1 g.'(85%) of 2-diethylaminoethyl l-hydroxyl-cyclohexyl) (p-xenyl) acetatehydrochloride, M.P. 168-170 C. when recrystallized T, from isopropylalcohol. Analysis.Calcd. for C H O NCl: Cl, 7.95; N, 3.14. --,Found:'Cl,8.00; N, 3.10.

' funnel and stirrer.

Magnesium (4.9 g., 0.2 mole) was placed in a thoroughly driedthree-neckedflaskfitted with a condenser, dropping Enough dry ether wasadded to cover the magnesium followed by the addition of 1 cc. of ethylbromide. After the reaction had been initiated there were added,successively, about 150 cc. of dry ether and 15.8 g. (0.1 mole) ofsodium phenylacetate (which had been dried at 130 C.). The mixturewasstirred, and 15.7 f. (0.2 mole) of isopropyl chloride, dissolved in50cc. of. dry ether, was added dropwise at such a rate that the mixturecontinued to reflux. After the addition 'or theisopropyl chloride, themixture was stirred and refluxed until-no more gas was evolved (abouttwo to two and one-halfhours). The mixture was cooled to about 10 C.and, with stirring 15.8 g. (0.22 mole) of isobutyraldehyde in 50 cc. ofdry ether was added dropwlse. refluxed for two hours, then cooled andhydrolyzed by After the addition was completed the mixture was verycareful addition of water followed by dilute hydrochloric acid. Theether layer was separated, and the aqueous layer was extracted withether. The combined ether layers were then extracted wtih sodiumcarbonate solution. The basic extracts were combined and carefullyacidified with dilute hydrochloric acid. The acidic material whichseparated was extracted several times with ether and the combined etherextracts were dried over anhydrous magnesium sulfate. The ether wasremoved by distillation and the residue was recrystallized from toluene,giving 13.1 g. (63%) of 2-phenyl-3-hydroxy-4-methylpentanoic acid, M.P.126-127 C.

Neut. equiv. calcd. for C H 5O 208.3. Found: 208.8.

(b) 2 diethylaminoethyl 2 phenyl 3-hydroxy-4- methylpentanoate:

' (EH3 CaHs CHaGHClI-CH-G O O OHzCHzN(C-.*Hs)2 (94.2%) ofZ-diethylaminothyl 2-phenyl-3-hydroxy-4- methylpentanoate hydrochloride,M.P. 117-121 C. when recrystallized from a butyl alcohol-isopropyl ethermixture.

Analysis.-Ca1cd. for C H O NCI: Cl, 10.31; N, 4.07. Found: Cl, 10.30; N,4.06.

2 diethylaminoethyl 2 phenyl-3-hydroxy-4-methylpentanoate hydrochloridewas found to have an antispasmodic activity about 12% that of atropinesulfate when tested by the modified Magnus method [Luduena and Lands, IPharmacol. and Exptl. The'rap. 110, 282 (1954)].

A portion of the hydrochloride obtained above was converted to the freebase by treatment with aqueous sodium carbonate and extraction withether. A solution of 3.0 g. of the free base in alcohol in ethersolution was treated with 25% excess of methyl bromide. The 3.2 g. ofwhite crystalline compound which precipitated was collected byfiltration, washed with ether and recrystallized from acetone, givingZ-diethylaminoethyl 2- 'pentanoate methobromide was found to have anantispasmodic activity about 11% that of'atropine. sulfate when EXAMPLE9 (a) Z-phenyl-B-hydroxy-4-ethylhexanoic acid was prepared starting with4.9 g. (0.2 mole) of magnesium,

15.8 g. (0.1 mole) of sodium phenylacetate in 150cc.

of ether, and 15.7 g. (0.2;mole) of isopropyl chloride in 50 cc. ofether according to the method described in Example 1, part (a). Afterthe mixture had refluxed for three hours, it was cooled to 10 C., and22.0 vg. (0.22 mole) of Z-ethylbutyraldehyde in 50 cc. ofether wasadded. The preparation was continued and worked up as described inExample 1, part (a) giving 17.5 g. (74%) -of 2.phenyl-3-hydroxy-4-ethylhexanoic acid, M.P. 98-1 O C. afterrecrystallization from a toluenepetroleumether mixture.

Neut. equiv. 'Cald. for C I-I 0 236.3. Found: 235.6.

(b) 2 diethylaminoethyl 2 phenyl-3-hydroxy-4- ethylhexanoate:

QHaCHZ G 5 OHCH-CHF-C O O CHzCH2N(C:H5)I

I CHaCHa DE A solution of 5.2 g. (0.022 mole) of 2-phenyl-3--hydroxy-4-ethylhexanoic acid, as prepared in part (a) above, and 3.7 g.(0.027 mole) of 2-diethylaminoethyl, chloride in 75 cc. of isopropylalcohol was refluxed for 2.7% that of atropine sulfate-when testedby-the modified -Magnus method.

' EXAMPLE (a) 2-phenyl-3-methy1-3-hydroxypentanoic acid .was preparedstarting with 4.8 g. (0.2 mole) of magnesium,

15.8 g. (0.1 mole) of sodium phenylacetate, 15.7 g. (052 mole)of'isopropyl chloride and 200 cc. of ether according'to the methoddescribedin Example 1,-part (a). After the mixture had refluxed for fourhours, it was cooled to 10 C., and 15.8 g. (0.22 mole) of 2-butanone wasadded. The preparation was continued and worked up as described inExample 1, part (a), giving 15.2 g. (72.9%) of 2-phenyl-3-methyl-3hydroxypentanoicv acid,

M.P. 89-91 C. when recrystallized from ,a benzenepetroleum ethermixture.

Neut. equiv. calcd. for C H O 208.3. Found:'210.0. (b)Z-diethylaminoethyl 2-pheny1-3-methyl-3-hydroxypentanoate:

;A solution of 5.2 g. (0.025 mole), of ;2.-phenyl-3-methyl- '3hydroxypentanoic acid,. as prepared in part (q) above, and 4.05 g. (0.03mole) of 2-diethylarninoethyl chloride in 100 cc. of isopropyl alcoholwas refluxed for seven hours, filtered, and the solvent distilled underreduced pressure. The residue was rubbed under ether, and the resulting6.8 g. (79%) of white ,solid was collected by filtration giving2-diethylaminoethyl 2-phenyl-3-methyl-3- hydroxypentanoatehydrochloride, M:.P.';9 6,+9 8 C. when recrystallized fromanethylalcohol-ether mixture.

ml. of anhydrous benzene. refluxed for sixteen hours. -.to a volume ofabout 1500 ml. by the addition of an- .hydrous ether, was addeddropwise, a solution of 40 g. (0.55 -mole) ofzbutyraldehyde in 500 ml.of anhydrous Analysis.--Calcd. unc t-1 0mm Cl, '1'j0.3i1 54.07. Found:Cl, 10.26; N, 4.09.

2-diethylaminoethyl 2-phenyl-3-methyl-3-hydroxypentanoate hydrochloridewas found to have an antispasmodic activity about 7% that of atropinesulfate when tested by the modified Magnus method. The intravenous ALDvalue in mice was 53 mg./kg. 7

EXAMPLE 11 (a) 2-phenyl-3-ethyl-3-hydroxypentanoic acidwas preparedstarting with 7.3 g. (0.3 mole) of magnesium, 23.7 g. (0.15 mole) ofsodium phenylacetate in 200 cc. of ether, and 23.6 g. (0.3 mole) ofisopropyl chloride in cc. of ether according to the method described inExample 1, part (a). After'the mixture had refluxed for three hours, itwas cooled to 10 C., and 28.4 g. (0.33 mole) of diethyl'ketone wasadded.The-preparation was continued and worked up as described in Example 1,part (a) giving 27.2 g. (81.6%) of 2-phenyl-3-ethyl-3-hydroxypentanoicacid, M.P. 151-l52 C. when recrystallized from alcohol.

Neut. equiv. calcd. for C H 'O 222.3. Found. 223.1.

(b) 2 diethylaminoethyl 2 phenyl 3 ethyl 3 hydroxypentanoate:

CHaCHr 0 5 o H-o o 0 CHzCH-2N(C2H5)2 c1330 2 on noate hydrochloride wasfound to have an antispasmodic activity about 3% that of atropinesulfate when tested by the modified Magnus method. The intravenous ALD'.value in mice was 53 mg./ kg.

EXAMPLE 12 (a) ,2-phenyl-3-hydroxyhexanoic acid: To a stirred solutionof isopropylmagnesium chloride [approximately 1 mole, preparedfrom 24.3g. (1.0 mole) of magnesium turnings and 90 g. (1.15 moles) of isopropylchloride] in 1200 ml. of anhydrous ether vwas added, dropwise, asolution of 68.1 g. (0.5 mole) of phenylacetic acid in 300 The mixturewas stirred, and The cold mixture, adjusted ether. "Ihestirred mixturewas refluxed for three hours, :then cooled and poured into a mixture ofml. of concentrated hydrochloric acid and about 800 g. of ice withvigorous stirring to bring about hydrolysis of the .Grignard complex."The-benzene-ether layer was separated, washed with water, and extractedwith a cold solution of 1.2 moles of sodium bicarbonate in 1 liter ofwater. The alkaline extract was washed with ether, cooled, and acidifiedwith concentrated hydrochloric acid. The product which separated wascollected by filtration, dried thoroughly in vacuo, andrecrystallizedfrom methyl ethyl ketone,giving 66.5 g. (64%) of2-phenyl-3-hydroxyhexanoic acid, -M.P. 152-154 C.

Analysis.-Calcd. for C H O C, 69.20; H, 7.75. ,Found: C, 69.29;,H, 7.99.Neut. equiv. calcd.: 208.3. Found: 207.6.

5 (b) 2-diethy1aminoethy1 Z-phenyl-3-hydroxyhexanoate:

ethyl chloride which had previously been dissolved in its own weight ofanhydrous benzene. The solution was refluxed for an additional eighthours, and then filtered while hot to remove the small amount ofself-condensation product of the Z-diethylaminoethyl chloride whichusually formed during the course of. the reaction. The

cooled solution was diluted with anhydrous ether until the product beganto separate, and then cooled at C.

for about sixteen hours. The product was collected by filtration, washedwith anhydrous ether, and recrystallized from an isopropylalcohol-methyl ethyl ketone mixture, giving 9.6 g. (70%) ofZ-diethylaminoethyl 2-phenyl- .3-hydroxyhexanoate in the form of itshydrochloride salt, M.P. 117-119 C.

Analysis.Calcd. for C H O NCl: C, 62.87; H, 8.79; N, 4.07; Cl, 10.31.Found: C, 62.60; H, 9.08; N, 4.00; Cl, 10.24.

Z-diethylaminoethyl 2-phenyl-3-hydroxyhexanoate hydrochloride was foundto have an antispasmodic activity about 25% that of atropine sulfatewhen tested by the modified Magnus methd. The intravenous ALD value inmice was 60 mg./kg.

A portion of the Z-diethylaminoethyl 2-phenyl-3-hydroxyhexanoatehydrochloride obtained above was converted to the free base by treatmentwith a slight excess of cold aqueous sodium carbonate and the free basewas extracted with ether. The ether solution was dried and treated witha fourfold excess of methyl bromide at room temperature. After standingfor twenty-four hours, the solution was cooled to 0 C. for from one totwo days.

The crystalline material which separated was collected by filtration andrecrystallized from an isopropyl alcoholmethyl ethyl ketone mixture togive Z-diethylaminoethyl 2-phenyl-3-hydroxyhexanoate in the form of itsmethobromide salt, M.P. 135136 C.

Analysis.-Calcd. for C H O NBr: C, 56.71; H, 8.02; N, 3.48; Br, 19.86.Found: C, 56.42; H, 8.04; N, 3.52; Br, 19.78.

Z-diethylaminoethyl 2 phenyl 3 hydroxyhexanoate 'methobromide was foundto have an antispasmodic activity about 10% that of atropine sulfatewhen tested by the modified Magnus method. The intravenous ALD value inmice was 18 mg./kg.

EXAMPLE 13 (a) 2-phenyl-3-hydroxyoctanoic acid was prepared 7 fromisopropylmagnesium chloride, phenylacetic acid and l-hexanal accordingto the manipulative procedure described above in Example 12, part (a).There was thus obtained 2-phenyl-3-hydroxyoctanoic acid in 53% yield,

M.P. 11011l C. when recrystallized from benzene.

- was prepared from 2-pl1enyl-3-hydroxyoctanoic acid and2-diethylaminoethyl chloride according to the manipula-' tive proceduredescribed above in Example 12, part (b).

The hydrochloride salt of Z-diethylaminoethyl Z-phenyl-S-hydroxyoctanoate was obtained in 80% yield and had the M.P. 106-107 C.when recrystallizedfrom a benzene-ether mixture.

12 AnalysisI-Calcd. for C H ;O NCl: C, 64.59; H, 9.21;

N, 3.77; Cl, 9.53. Found: C. 64.47; H, 9.19; N, 3.79; CI, 9.47.

The methobromide salt of 2-diethylaminoethyl Z-phenyl-3-hydroxyoctanoatehad the M.P. 101-103 C. when recrystallized from an isopropylalcohol-ether mixture.

Analysis.Calcd. for C H O NBr: C, 58.60; H, 8.43;

I "N, 3.25; Br, 18.57. Found: C, 58.76; H, 8.64; N, 3.26;

EXAMPLE 14 a) 2-phenyl-3-hydroxynonanoic acid was prepared fromisopropylmagnesium chloride, phenylacetic acid and l-heptanalaccordingto the manipulative procedure described above in Example 12, part (a).The 2-phenyl-3- hydroxynonanoic acid was obtained in 69% yield and hadthe M.P. 109-111 C. when recrystallized from a methyl ethylketone-petroleum ether mixture.

Analysis.--Calcd. for C H O C, 71.96; H, 8.86. Found: C, 72.37; H, 9.10.Neut. equiv. calcd.: 250.3. Found: 250.0.

(b) 2- diethylaminoethyl 2-phenyl-3-hydroxynonanoate:

011301120momornomon-on-oo0omommomn, 1 11 was prepared from2-phenyl-3-hydroxynonanoic acid and Z-diethylaminoethyl chlorideaccordingto the manipulative procedure described above in Example 12,part (b). The hydrochloride salt of Z-diethylaminoethyl Z-phenyl-3-hydroxynonanoate was obtained in 68% yield and had the M.P. 102l03 C.when recrystallized from 3. benzene-ether mixture.

, AnaZysis.-Calcd. for C H O NCl: C, 65.35; H, 9.40; N, 3.63; Cl, 9.18.Found: C, 65.30; H, 9.46; N, 3.60;

in mice was 31 mg./kg.

The methobromide salt of Z-diethylaminoethyl 2-pheny1-3-hydroxynonanoatehad the M.P. Ill-113 C. when recrystallized from an isopropylalcohol-ether mixture.

Analysis..Caicd.for C H O NBr: C, 59.45; H, 8.62; N, 3.15; Br, 17.98.Found: C, 59.11; H, 8.59; N, 3.14;

Z-diethylaminoethyl 2 phenyl 3 hydroxynonanoate methobromide was foundto have an antispasmodic activity about 53% that of atropine sulfatewhen tested by the modified Magnus method. The intravenous ALD value inmice was 6 mg./kg.

' EXAMPLE 15 (a) 2-phenyl-3-hydroxy 3 methylnonanoic acid was preparedfrom isopropylmagnesium chloride, phenylacetic acid andZ-methyl-l-heptanal according to the manipulative procedure describedabove in Example 12,

part (a).

(b) Z-diethylamindethyl 2-phenyl-3-hydroxy-3-methylnonanoate:

on. can. GHiQHQH,OHrGH,CH,J J-GHCooonicmmoznm 0H was prepared from2-phenyl-3-hydroxynonanoic acid and Z-diethylaminoethyl chlorideaccording to the manipulative procedure described above in Example 12,part (b). The hydrochloride salt had the M.P. 98 C. when recrystallizedfrom ethyl acetate.

Analysis.-Calcd. for C H O NCl: C, 66.05; H, 9.58;

: Cl, 8.87. Found; C, 65.80; H, 9.60; CI, 9.10.

EXAMPLE 16 Y (a) a Phenylai-( 1-hydroxy 2-methylcyclohexyl)acetic acid:To a'stir'red solution'ofisopropyl magnesiumchloride (approximately 1mole, prepared from 24.3 g. (1.0 mole) of magnesium turnings and 90 g.(1.15 moles) of isopropyl chloride) in 1200 ml. of anhydrous ether wasadded, dropwise, a solution of 68.1 g. (0.5 mole) of phenylacetic acidin 300 ml. of anhydrous benzene. The mixture was stirred and refluxedfor sixteen hours. To the cold mixture, adjusted to a volume of about1500 ml. by the addition of anhydrous ether, was added, dropwise, asolution of 62 g. (0.55 mole) of 2-methylcyclohexanone in 500 ml. ofanhydrous ether. The stirred mixture was refluxed for three hours, thencooled and poured into a mixture of 125 ml. of concentrated hydrochloricacid and about 800 g. of ice with vigorous stirring to bring abouthydrolysis of the Grignard complex. The benzeneether layer wasseparated, washed with water, and extracted with a cold solution of 1.2moles of sodium bicarbonate in 1 liter of water. The alkaline extractwas washed with ether, cooled, and acidified with concentratedhydrochloric acid. The product which separated was collected byfiltration, dried thoroughly in vacuo, and recrystallized from methylethyl ketone, giving 48 g. (39%) of a-phenyl-a-(1-hydroxy-2-rnethylcyclohexyl) acetic acid, M.P. 126129 C.

Analysis.-Calcd. for C H O C, 72.55; H, 8.12. Found: C, 72.61; H, 8.13.Neut. equiv. calcd.: 248.3. Found: 247.4.

([2) 2 diethylaminoethyl on phenyl a (1 hydroxy-2-methylcyclohexyl)acetate:

was prepared from a-phenyl-u-(1-hydroxy-2-methylcyclohexyl)acetic acidand Z-diethylaminoethyl chloride according to the manipulative proceduredescribed in Example l, part (b). The hydrochloride salt ofZ-diethylaminoethyl a-phenyl-a-( 1-hydroxy-2-rnethylcyclohexyl) acetatethus obtained had the M.P. 158160 C. when recrystallized from anethanol-ether mixture.

Analysis.-Calcd. for C H O NCl: C, 65.69; H, 8.93; N, 3.65; Cl, 9.23.Found: C, 65.80; H, 8.92; N, 3.62; Cl, 9.27. v

(c) The methobrornide salt of Z-diethylmainoethylaphenyl-H1-hydroxy-Z-methylcyclohexyl)acetate was prepared as follows:the hydrochloride salt obtained in part (b) above was treated with aslight excess of cold aqueous sodium carbonate and the free base thusliberated was extracted with ether. The ether solution was dried andtreated with a fourfold excess of methyl bromide at room temperature.After standing for one day the solution was kept at 0 C. for one or twodays. The product which separated was collected by filtration andrecrystallized from an ethanol-ether mixture, giving the methobrornidesalt of Z-diethylaminoethyl.ot-phenyl-a-(l-hydroxy-2-methylcyclohexyl)acetate having the M.P. 190192 C.

Analysis.Calcd. for C H O NB1: C, 59.71; H, 8.21; N, 3.17; Br, 18.06.FoundaC, 59.54;:H, 8.24; N, 3.15; Br, 17.90.

1 4 The -.-methobromide salt of 2-diethylaminoethyl a" phenyl-,a-(lhydroxy 2 methylcyc1ohexy)acetate was found to have an antispasmodicactivity about 32.4%.that

.of atropine sulfate whentested by the modified Magnus method. Theintravenous ALD value in mice was 9 mg./kg.

The following additional a-phenyl-u-(l-hydroxy-cycloalkyl)acetic acidswere prepared by reacting isopropyl magnesium bromide, phenylaceticacid, and the appropriate cycloalkanone, according to the manipulativeprocedure described above in Example 16, part (a):

* Recrystallized from methyl ethyl ketone. b Recrystallized fromtoluene. c Recrystallized from benzene-petroleum ether (30-40).

Table 1 (b) ANALYSIS OF INTERMEDIATE ACIDS Neut. Equiv. Carbon HydrogenOom- Formula pound Calcd. Found Oalcd. Found Oalcd. Found 1 O 5HzuO3248.3 249.0 72.55 72.68 8.12 8.20 2.. O Hz O 248.3 248.0 72. 55 72:368.12 8.27 3 CmHzzO 262.3 262.3 73.26 73.42 8.45 8. 36 0 111 0 248.3248:9 72. 55 72.71 8.12 8.35

droxycycloalkyD-acetic acid with the appropriate tertiaryaminoalkylhalide. The resulting hydrohalide salt was neutralized, followed byquaternization of the resulting basic ester with theappropriatequaternizing agent, all

according to the manipulative procedures described above in parts (b)and (c) of Example 1.

Table 2(a) CflHi RCHCOOYN=B-RX Example R YN=B RX M.P., O.

/CH2CE2 /OH 17 Cs; 0 CH2CHzN(C2H5) HCL. -152 (IJHCHz C 3 Recrystallizedfrom methyl ethyl ketone.

9 Becrystgllized from isopropyl alcohol.

7 Recrystallized from methyl ethyl ketone-ethanol.

1 Recrystallized from m'eton'e.

Example R YN=B RX M42, o 0.'

omom OH I 18 CH2 0 OH2CHzN(CzH GHaB 195-196 mom CH3 01120112 011 19 0g,0 cmommomm CHz=CHOHzBr =14a-14s (\JHOHf CH3 GHzCgz OH 20 011 03 ccmommczm HCL- M54456 CHzCHz /CHzCH2 H 21 011 011 /0 cn ommcmm, 0mm194-196 01310112 /OH 22 CHgCH C OHgCH2N( 2H5)2 ni CH2=CHCH2B1..--153-155 CHzCHz 3 011mm 011 i 23 5, 0 omomNwzHm CqHgOOCHzBL---20()202(dec.)

CHzOz 24 0 a c CmcHzNwzm 02mm -178 CHzQl CHzCHz /OH I 25 0%] CCHZCH2N(CQH5)2 CHz=CHCH2Br I"152-154 I omcHf omega 0E 26 0\ CcHgcHaNwam): -J. CflH5CH2 lm-1740180.)

CHzCHz 013mm 011 21 c CHQCHZI\I(C2H5): 011301 mas-mo CHzCHz CHzCHzCHa OH28 CH2 0 0H;CHzN(C2H )z H01 144-146 omomcm CHzCHaCEIJ /OK 29 c a c.cmcmmmmn -Q 0mm mas-15s CHzCHaCHn CHQCHZCEH /OH so o CHZCHZNWQHEM H01142-143 mcmom omcmcm 0H 7 a a1 c omcmmmm 0113131 14-115 HzCHaCz omcmcn,OH 3111 01120112 32 c omcmN /CH2 H01 im-173.5

HzCHzCz CHaGHzCHz 01120320112 0H 0115011103,, as c 01120112: /CH2 0mm196(dec.) 11201120112 011201120132 acid and 12-.piperidinoethyl halide.

. .noate: 011.0 9.0111 can. 0115011,

' o-oH-oooomomN by reaction of 2-phenyl-3-hydroxy-3-ethylhexanoic acidand 2-pyrrolidinoethyl halide. Said acid can be prepared by reaction ofthe Grignard derivative of phenylacetic acid andethyl propyl ketone.

2 piperidinoethyl Z-(Z-thienyl)-3-hydroxyr3-ethylpentanoate:

CH3CH3 OHZCH! C-CH-COOCHzCHaN CH2 CHsC: OH CHzCi by reaction of-2-(2-thienyl)-3-hydroxy-3-ethylpentanoic Said acid can be pre- Table,2'(b) ANALYSlS F oo'MPoUNDsbF TABLE "2(a) Carbon Hydrogen NitrogenHalogen Example Formula 1 Calcd. Found Calcd. Found Calcd. Found Caled.Found C2lH3403N01 55.59 55. 78 8.93 9. 00 3.55 3.70 9. 23 9.15cziHaoaNBr 59:71. 59.97 8. 21- 8.32 3.17 3.15 18.06 18.00 CzaHaaOaNBr51. 53 51. 27 8. 18 8.35 2. 99 2. 91 17. 17.00 C21H5703N01 3. 55- 3. 519. 23 9.21 C22HasOsNBr 59:71 59. 93 8. 21 8. 25 3. 17 3. 18. 05 18.00C24Has03NBr 51.53 51.27 8.18 8.21 2.99 2. 92 17.05 17.01 G28HasO4NBr53.15 53. 02 7; 19 4 7. 05 2.53 2:58 15. 01 v 14.94- C2zH85OsNBr 59.7259.35 8.20 8.58 3.17 3.14 18.05 18.00 CzaHsaOsNBr 50. 78 50.52 8.00 8.143. 08 3. 04 17. 58 17. 52 O27Ha9OaNBr 54.28 54. 31 7.59 7.72 2.78 2.7515.84 15.85 0211311031201 3. 55 3. 51 9. 23 9. 43 CnHasOaNGl H 3. 52 3.54 8. 91 8. 97 CZIHaBOsNBl 50. 51 50. 58 8. 39 8. 45 3. 07 3. 15 17. 5117. 45 C2iH340aNC 3. 55 3. 54 9. 24 9. 32 O22H39OaNBt---- 1 3. 17 3. 2018. 06 17. 97 O21Ha8O3NC 57.98 58.00 9.03 9.23 8.85 8. 47 C25H1501NB7---52.23 52.47 8.36 8.31 15.55 15.71

Table 2(a) pared by reaction of the Grignard derivative of Z-thienyl-ACTIVITY AND TOXICITY OF QUATERNARY COMPOUNDS acme-Laud m y 9 v3-dibuty1am1nopropyl 2-pheny1-3 hepty1-3 -'hydroxy-de- Antisfias- T xi t25 63110816 Y I m0 0 0 01 y Example Activity tur CHKOHmOHZ 4 $3553 CCH-C 0 o omomomNwtm oHflcHahoz OH is g by reaction of2-phenyl-3-heptyl-3-hydroxydecanoic acid 21 80 9 anddibi1tylan1i-nopropylhalide. Said acid can be pre- 3; g

pared by reaction of the-Grignardxderivative of phenylgg (1)18 16 acetic:acid and di n-heptyl ketone. A 26 7 7 5 g 2-morpholinoethylZ-(p-methoxyphenyl) -.3v hydroxy-3- 27 5 1 r0 -4-me h l entano 29 53 135 isop pyl t yp ate 31 41 10 OCH: 33 5 By the methods described in thepreceding examples, CH the followingcompounds can also be prepared: l 3p Z-diethylamino 1 methyl'ethyl 2.(2-naphthyl)-3-hy- 5 2 3:droxyoctanoate: C-CH0 O 0 OH2OH2N /0 0115011 011 GHiOHi by reaction ofZ-(p-methoxyphenyl)-3-hydroxy-3-isopro-' pyl-4-methylpentanoic acid andZ-morpholinoe'thyl halide. Said acid can be prepared by reaction of theGrignard derivative of p-methoxyphenylacetic acid and diisopropylketone.

2-dirnethylaminoethyl 2-(o-tolyl) -3 -'hydroxyundecylate:

CHuomncmon-oH-Cooomommonor OH t i by reaction of2-(o-tolyl)-3-hydroxyundecylic acid and 2-dimetl1ylaminoethyl halide.Said acid can be prepared by reaction of the Grignard derivative ofo-tolylacetic acid and n-nonyl aldehyde.

Z-diethyIamioethyl2-(p-methylmei'captophenyl)-3-hydroxy-4-methylpentanoate:

SCH:

CH2 CH3( )HCHCHG 00 oniommoifisjz 511 by reaction of2-(p-rnethylmercaptophenyl)-3 hydroxy-4- methylpentanoate andZ-diethylaminoethyl halide. Said acid can be prepared by reaction of theGrignard derivative of p-methylmercaptophenylacetic acid andisobutyraldehyde.

acetate:

CHzCHz Co s C-CH-C O O GH2CHzCHzCH2CHzN(GHz)2 by reaction of(l-hydroxycyclopentyl) -phenylacetic acid and S-dimethylaminopentylhalide.

Z-diethylaminoethyl (5-methyl-2-thienyl) l-hydroxycyclohexyl) acetate:

/CH2OEI CH: C--- 11-0 O CHZCH2N(C2H5)1 omom OH by reaction of(-methyl-2-tbienyl)-(l-hydroxycyclohexyD-acetic acid andZ-diethylaminoethyl halide.

2 heptamethyleniminoethyl (1 hydroxycyclohexyD- phenylacetate:

/CH:CH GOES Cg: C---CHC O 0 CHQCHgN /CH2 CHsCH: OH GH CHzCHz by reactionof (l-hydroxycyclohexyl)-phenylacetic acid and 2-heptamethy1eniminoethylhalide.

2- diethylaminoethyl 1-hydroxy-4-methylcyclohexyl)-pmethoxyphenylacetate:

our-o o--- 11-0 0 0 cmommoznm CHaC; 011

by reaction of (1-hydroxy-4-methylcyclohexyl)-p-meth oxyphenylaceticacid and Z-diethylaminoethyl halide.

S-dimethylaminophenyl a-(l-hydroxycyclopentyl) uphenylacetatebenzochloride:

CHzOHZ C5115 O5 sCH2 CCH-C0 0 CHzCHzCHaCHzCHglTKCHz); among 0H 01 V byreaction of a-(l-hydroxycyclopentyl)-a-pheny1acetic acid andS-dimethylaminopentyl halide, and quaternization of the product withbenzyl chloride.

This application is a continuation-in-part of my prior applicationsSerial Number 540,147 and Serial Number 540,148, filed October 12, 1955,which are in turn continuations-in-part of my prior application SerialNumber 215,869, filed March 15, 1951; and all of which applications arenow abandoned.

I claim: 1. A member of the group consisting of (A) compounds having theformula .i lr R-oH-o 0 O-YN=B wherein Ar a member of the groupconsisting of aromatic carbocyclic radicalsof 1-2 rings having less thancarbon atoms, Z-thienyl, 3-thienyl, and lower-alkylatcd thienyl; Y is alower-alkylene bridge having from 2 to 5 carbon atoms; -N=B is selectedfrom the group consisting of di-lower-alkylamino, 5- to S-memberedpolymetheneimino rings, lower-alkylated-S- to S-memberedpolymethyleneimino rings, and morpholino; and R- is a member 'of thegroup consisting of l-hydroxyalkyl hav- S-dimethylaminopentyll-hydroxycyclopentyl) -phenylwherein Y is a lower-alkylene bridge havingfrom 2 to ing from 4 to 15 carbon atoms, and, l-hydroxycycloalkyl havingfrom,5 to lO carbon atoms, the cycloalkyl ring having from 5 to 8 carbonatoms; (B) acid-addition salts thereof; and (C) quaternary ammoniumsalts thereof.

2. A compound having the formula I 'phenyl ROHC o O-YN=di lower-alkyl Vwherein Y is a lower-alkylene bridge having from 2.to

5 carbon atoms, and R is l-hydroxyalkyl having from 4 to 15 carbonatoms.

3. A compound having the formula phenyl I v V R-CHCOO QH2CH2N(C2H5)2wherein R is l-hydroxyalkyl having from 4 to 15 carbon atoms. 7

r 4. A compound having the formula 5 carbon atoms, and n is an integerfrom 1 to 2.

5. 2-diethylaminoethyl 2-pheny1-3-hydroxy-4-methylpentanoate having theformula CHaCHz phenyl CH1 C OHC O OYN=di lower-alkyl CHBCHI OH wherein Yis a lower-alkylene bridge having from 2 to 5 carbon atoms.

10. A compound having the formula OH201\I;4 phenyl o-cH-c 0 O-YN=dilower-alkyl cut-cm on wherein Y is a lower-alkylene bridge having from 2to 5 carbon atoms.

11. Z-diethylaminoethyl (1 hydroxy 1 cyclohexyl)- phenylacetate havingthe formula 12. Z-diethylaminoethyl (l-hydroxy-l-cyclohexyl)-(2-thienyl)acetate hydrochloride.

13. Z-diethylaminoethyl 2-phenyl-3-ethyl 3 hydroxypentanoatehydrochloride.

14. A Z-diethylaminoethyl 2-phenyl-3-hydroxyhexanoate hydrochloride.

15. The compound:

in which A is a group selected from the class consisting ofl-hydroxycyclohexyl and alkyl-substituted 1-hydroxycyclohexyl groups, nis a whole number varying from 2 to 5, M is a quaternary ammonium saltmoiety, and B is a radical selected from the class consisting of phenyland alkoxyphenyl radicals, said alkyl and alkoxy groups each containing1 to 6 carbon atoms.

16. The compound:

in which A is a member of the group consisting of 1- hydroxycyclohexyland alkyl-substituted l-hydroxycyclohexyl groups, n is a whole numbervarying from 2 to 5, R is an alkyl group, X is a halogen radicalselected from the group consisting of chlorine, bromine, and iodine, andB is a member of the group consisting of phenyl and alkoxyphenyl groups,said alkyl and alkoxy groups each containing 1 to 6 carbon atoms.

17. The compound of claim 16 in which A is a 1- hydroxycyclohexyl groupand B is a phenyl group.

18. The compound of claim 16 in which A is an alkylsubstitutedl-hydroxycyclohexyl group and B is an alkoxyphenyl group.

19. The quaternary ammonium compound:

in which A is a group selected from the class consisting ofl-hydroxycyclohexyl and alkyl-substituted l-hydroxycyclohexyl groups, Ris a bivalent radical containing only carbon and hydrogen and having 2to carbon atoms and being derived from an aliphatic hydrocarbon byremoval of a hydrogen atom from each of two terminal carbon atoms, R isan alkyl group, R is a univalent radical containing only carbon andhydrogen and being selected from the group consisting of alkyl andaralkyl radicals, X is an anionic moiety selected from the groupconsisting of a halogen radical, ArSO and RS0 where Ar is aryl and R isalkyl, said halogen radical being a member of the group consisting ofCl-, Br-, and I-, and B is a radical selected from the class consistingof phenyl and alkoxyphenyl radicals, said alkyl and alkoxy groups eachcontaining 1 to 6 carbon atoms.

20. The methobromide of beta-(diethylamino)ethyl ester of2-phenyl-2-(l-hydroxycyclohexyl)ethanoic acid.

2.1. The methohalide of beta-(diethylamino)ethyl ester of2-phenyl-2-(l-hydroxycyclohexyl)ethanoic acid, said halide moiety beinga member of the group consisting of chloride, bromide, and iodide.

22. The compound:

in which A is a group selected from the class consisting ofl-hydroxycyclopentyl and alkyl-substituted l-hydroxycyclopentyl groups,n is a whole number varying from 2 to 5, M is a quaternary ammonium saltmoiety, and B is a radical selected from the class consisting of phenyland alkoxyphenyl radicals, said alkyl and alkoxy groups each containing1 to 6 carbon atoms.

23. The compound:

A(]3HCOO(CH2),,N(R)3.X

in which A is a member of the group consisting of 1- hydroxycyclopentyl'and alkyl-substituted l-hydroxycy in which A is a group selected fromthe class consisting of l-hydroxycyclopentyl and alkoXy-substitutedl-hydroxycyclopentyl groups, R is a bivalent radical containing onlycarbon and hydrogen and having 2 to 5 carbon atoms and being derivedfrom an aliphatic hydrocarbon by removal of a hydrogen atom from each oftwo terminal carbon atoms, R is an alkyl group, R is a univalent radicalcontaining only carbon and hydrogen and being selected from the groupconsisting of alkyl and aralkyl radicals, X is an anionic moietyselected from the group consisting of a halogen radical, A and RS0;where Ar is aryl and R is alkyl, said halogen radical being a member ofthe group consisting of Cl-',

Br, and I-, and B is a radical selected from the class consisting ofphenyl and alkoxyphenyl radicals, said alkyl and alkoxy groups eachcontaining 1 to 6 carbon atoms.

1,987,546 Blankart Jan. 8, 1935 2,490,964 Hofimann Dec. 13, 1949 FOREIGNPATENTS 505,276 Belgium Dec. 1, 1951 OTHER REFERENCES Ford: Journal ofthe Chemical Society (1947), pp. 56, 58 and 59.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No.2,922,795 January 26, 1960 Frederick F. Blicke It is hereby certifiedthat error appears in the printed specification of the above numberedpatent requiring correction and that the said Letters Patent should readas corrected below.

Column 1, line 70, for -C(OH CH read -C(CH CH same line, for -CH(CH)CH(CH read -CH(OH )CH(CH column 2, line 25, for l-hdroxydecyl read1-hydroxydecyl; lines 38 and 39, for 3-methyl-1-hydroxycyclohexy read3-methyl-1-hydroxycyclohexyl; column 6, line 12, for S H O S read O H OS lines 16 to 22, the formula should appear as shown below instead of asin the patent:

same column 6, line 24, for (3-thienyl) acetate acid read (S-thienyl)acetic acid line 73, for (2-thienyl-acetic read --(2-thienyl) acetic;line 75, for (2-thienyl aceread (2-thienyl)ace-; column 7, line 29, forcyclopenyl) read cyclopentyl)-; column 8, line 11, for 15.7 f. read 15.7g.; column 11, line 30, for methd read method; column 13, line 46, for2-diethylmainoethyl read -2diethylaminoethyl; column 141, line 2, for-2-methylcyclohexy) acetateread -2-methylcyclohexyl)acetate; columns 15and 16, Table 2(a), fifth column thereof, under the heading M.P., C.,last line, for 195196(dec.) read l95196(dec.); column 18, line 63, for2-diethylami0ethyl read 2-diethylaminoethyl; column 19, lines 6 to 9,the formula should appear as shown below instead of as in the patent:

CH2CH2 00H:

c-oH-ooocmcrnomomommcm),

H10 1 OH line 46, for 5-dime'thylaminophenyl read5-dimethylaminopentyl-; column 22, line 26, for alkoxy-substituted read-alkyl-substituted.

Signed and sealed this 6th day of September 1960.

[smifll Attest:

ERNEST W. SWIDER, ROBERT C. WATSON, Attesting Oyfioer. Gonwm'ssioner ofPatents.

1. A MEMBER OF THE GROUP CONSISTING OF (A) COMPOUNDS HAVING THE FORMULA